Viktoria Shihab, M.D., R.D., M.P.H. – Extern and Researcher
Sandy Elsabbagh, M.B.B.Ch.
Steven Lippmann, M.D. – Emeritus Professor, University of Louisville School of Medicine
Following its discovery in 1962, xylazine was trialed as an antihypertensive agent, but determined to be unsafe for human consumption.1-3 Ten years later, this pharmaceutical received approval to enter the market as a non-narcotic veterinary sedative, muscle relaxant, and analgesic.4 Since the early 2000s, xylazine has attracted attention as a dangerous opioid adulterant in Puerto Rico.2 By 2021, xylazine was detected in 91% of fentanyl and/or heroin samples in Philadelphia.2 Xylazine prevalence continues to rise and contribute to the danger of drug overdoses throughout the U.S.A., especially in the Northeastern states.2
Xylazine functions as an alpha-2A adrenergic receptor agonist, decreasing norepinephrine and epinephrine via a negative feedback mechanism and increasing the risk of bradycardia and hypotension.2 It also activates alpha-2B adrenergic receptors, constricting the peripheral skin vasculature.5,6 Its sympatholytic properties combined with vasoconstriction often result in cutaneous pathology with infection. Xylazine is notorious for inducing ulceration, abscesses, and necrosis that may require surgical intervention. This side effect in users has earned xylazine its “zombie street drug” media name.5
The veterinary tranquilizer poses a high risk for treatment-resistant overdose. Naloxone, prescribed to treat opioid overdose, is much less effective in treating opioids mixed with xylazine as xylazine has no known antidote.7 Overdose deaths from fentanyl mixed with xylazine have increased by 276% from 2019 to 2022.8 This number might be underreported due to coroner inconsistency with testing for and reporting the drug on death certificates.8 Xylazine has an addiction potential. It is often mixed with opioids because it is cheap, poorly regulated, and potentiates the effect of narcotics; it can be acquired for <$20/kg from Chinese suppliers online.9 Often, many users are unaware of having ingesting it.4,10 Besides being added to narcotics, xylazine is frequently mixed with other drugs like cocaine, benzodiazepines, and ketamine; this further complicates clinical recognition and treatment of xylazine intoxication.10
For over a decade, xylazine has been identified as a major public health concern.11 In response to the rising fentanyl overdose crisis, in March 2023, the federal government called for an investment of >$46 billion in National Drug Control Programs.12 By April 2023, the government designated fentanyl combined with xylazine as an “Emerging Threat to the United States”.13 In July 2023, the White House Office of National Drug Control Policy released a National Response Plan.14 Under this proposal, various agencies are working to restrict xylazine’s entry into the U.S.A. and only for its intended veterinary purposes. However, online purchases remain difficult to regulate.4 The strategy also includes expanding xylazine research, standardizing the testing, reporting of cases, establishing an evidence-based treatment protocol, and developing an antidote. It also aims to educate the public, healthcare providers, and researchers about the dangers of this drug.14
References
1. Greene, S. A., & Thurmon, J. C. (1988). Xylazine–a review of its pharmacology and use in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 11(4), 295–313. https://doi.org/10.1111/j.1365-2885.1988.tb00189.x
2. Papudesi BN, Malayala SV, Regina AC. Xylazine Toxicity. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK594271/ Accessed November 8, 2023.
3. Ruiz-Colón, K., Chavez-Arias, C., Díaz-Alcalá, J. E., et al. (2014). Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature. Forensic Science International, 240, 1–8. https://doi.org/10.1016/j.forsciint.2014.03.015 Accessed November 8, 2023.
4. Forfa, T. (2023) What We’re Doing to Stop Illicit Xylazine from Getting into the U.S. U.S. Food and Drug Administration. https://www.fda.gov/animal-veterinary/news-events/what-were-doing-stop-illicit-xylazine-getting-us Accessed November 8, 2023.
5. Kanagy N. L. (2005). Alpha(2)-adrenergic receptor signalling in hypertension. Clinical Science (London, England): (1979), 109(5), 431–437. https://doi.org/10.1042/CS20050101
6. Malayala, S. V., Papudesi, B. N., Bobb, R., et al. (2022). Xylazine-Induced Skin Ulcers in a Person Who Injects Drugs in Philadelphia, Pennsylvania, USA. Cureus, 14(8), e28160. https://doi.org/10.7759/cureus.28160 Accessed November 8, 2023.
7. Alexander RS, Canver BR, Sue KL, et al.(2022). Xylazine and Overdoses: Trends, Concerns, and Recommendations. American Journal of Public Health 112(8):1212-1216.PMID:35830662 https://doi.org/10.2105/AJPH.2022.306881
8. Kariisa M, O’Donnell J, Kumar S, et al.(2023) Illicitly Manufactured Fentanyl–Involved Overdose Deaths with Detected Xylazine — United States, January 2019–June 2022. Morbidity and Mortality Weekly Report;72:721–727. DOI: http://dx.doi.org/10.15585/mmwr.mm7226a4 Accessed November 8, 2023.
9. Drug Enforcement Administration (2022). The Growing Threat of Xylazine and its Mixture with Illicit Drugs. https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf Accessed November 8, 2023.
10. Ayub, S., Parnia, S., Poddar, K., et al. (2023). Xylazine in the Opioid Epidemic: A Systematic Review of Case Reports and Clinical Implications. Cureus, 15(3), e36864. https://doi.org/10.7759/cureus.36864. Accessed November 8, 2023.
11. Reyes, J. C., Negrón, J. L., Colón, H. M., et al. (2012). The Emerging of Xylazine as a New Drug of Abuse and its Health Consequences among Drug Users in Puerto Rico. Journal of Urban Health, 89(3), 519–526. https://doi.org/10.1007/s11524-011-9662-6
12. The White House. (2023). President Biden Calls for Historic Funding to Beat the Overdose Epidemic Being Driven by Fentanyl. https://www.whitehouse.gov/ondcp/briefing-room/2023/03/09/president-biden-calls-for-historic-funding-to-beat-the-overdose-epidemic-being-driven-by-fentanyl/?utm_source=link Accessed November 8, 2023.
13. The White House. (2023). Biden-Harris Administration Designates Fentanyl Combined with Xylazine as an Emerging Threat to the United States. https://www.whitehouse.gov/ondcp/briefing-room/2023/04/12/biden-harris-administration-designates-fentanyl-combined-with-xylazine-as-an-emerging-threat-to-the-united-states/ Accessed November 8, 2023.
14. The White House.(2023). Fentanyl-Adulterated-Or-Associated-With-Xylazine-Emerging-Threat-Response-Plan-Report. https://www.whitehouse.gov/wp-content/uploads/2023/07/FENTANYL-ADULTERATED-OR-ASSOCIATED-WITH-XYLAZINE-EMERGING-THREAT-RESPONSE-PLAN-Report-July-2023.pdf Accessed November 8, 2023.
